In this interview we discuss new clinical guidelines from ASTRO on the use of radiotherapy in treating oropharyngeal cancer.
1. Could you give us some background on oropharyngeal squamous cell cancer? How frequently is this type of head and neck cancer diagnosed, and what is the prognosis for these patients?
DR. SHER: Oropharyngeal squamous cell cancer is a primary malignancy of the back of the throat, specifically the tonsils, base of the tongue, upper back of the throat, and soft palate. Historically, the disease was primarily caused by behaviors such as smoking and alcohol use. The prognosis over time has been very poor, and the key to understanding oropharyngeal squamous cell cancer is to understand that the epidemiology has changed dramatically.
It became recognized in the 1990s and 2000s that, more and more, oropharyngeal cancer was being driven by the human papillomavirus (HPV), and in 2017 that is the etiology of the vast majority of oropharyngeal tumors. In the last 10 years, the increase in oropharyngeal cancer has been somewhat dramatic, and it’s all due to the rising prevalence of HPV driving the disease. We estimate now that there are approximately 10,000 to 15,000 cases per year in the United States, and almost all of that increase is due to HPV, with the majority of cases in men. It’s increasing in women a bit, but much more so in men.
When someone comes into the clinic asking what their outcome is going to be, we have to get into what is causing the tumor. For patients with HPV-positive disease, which comprises about 70% to 80% of new diagnoses, the prognoses are actually quite good if not excellent. A high-level study that helped to redefine the staging of HPV-positive cancer has shown that for all-comers, as long as their disease isn’t gigantic, there is about an 80% survival rate at 5 years for almost any stage, which is quite good. You have to contrast that with patients whose disease is driven by smoking (HPV-negative disease). If you look at all comers who have a new diagnosis of HPV-negative cancer, the survival rate is less than 50% at 5 years and can be as low as 30% in patients who have the most advanced disease-big primary tumors and very large positive nodes. So, the prognosis discussion relates to the driving etiology of the disease, and ranges from very good to quite scary. It’s so different, in fact, that the new staging system differentiates the two types, HPV-positive and HPV-negative disease.
2. What is the typical treatment for patients with oropharyngeal cancer? What are the highlights of the updated American Society for Radiation Oncology (ASTRO) clinical guideline that you coauthored, as far as the standard of care with radiation therapy?
DR. SHER: The first decision that the treatment team and the patient have to make is whether the patient is going to have surgery or radiation therapy. It’s a very controversial question and there are strengths and weaknesses to both primary surgery and primary radiation. We did not, as a guideline panel, want to weigh in on this controversy, in large part because there are no data, mostly just opinions.
Patients who are treated with surgery are then treated with adjuvant radiation therapy or chemoradiation. For those treated with primary definitive radiation, there are many different “flavors” of that radiation therapy, whether with chemotherapy or in terms of the different ways it is delivered. In the guideline, we addressed all of these different possibilities to help guide the radiation and chemoradiation piece of the decision-making process.
The guideline is divided into four sections. In the first, we looked at patients being treated with radiation therapy, and one of the take-home messages is that the standard of therapy for locally advanced disease is chemoradiation with a bolus of cisplatin chemotherapy. That was chosen because it has been established over many years, in many prospective trials, and has been the most consistently tested chemotherapy regimen for oropharyngeal cancer. For patients who cannot tolerate that, we also made recommendations for concurrent systemic regimens, particularly cetuximab or carboplatin/fluorouracil, both of which have been shown to improve survival in randomized trials. Weekly cisplatin is also a viable regimen and is commonly used. We included this option but make the point that if it is used, it needs to be discussed with the patient that the supporting data are significantly weaker for weekly cisplatin than for the regimens that we strongly recommended. Another take-home message from this part of the guideline is that patients with lower-volume disease don’t need chemotherapy, and the recommendation is not to use routine chemoradiation in these patients (stage III).
The second section in the guideline looks at postoperative radiation. We didn’t address whether the patient should have surgery, but if he or she did have surgery, we made several recommendations on postoperative management, again relying on bolus cisplatin with radiation therapy as the strongest recommended treatment for patients with high-risk disease-mainly those with positive margins or extranodal extension on pathologic review. Weekly cisplatin may be used, but it is important to mention the lack of data there, and this should be pointed out to the patient in the discussion. For those who can’t tolerate a cisplatin-based regimen, the routine treatment that is recommended is radiation alone. Another important point is that for patients who don’t have high-risk disease, even if they have other intermediate-risk factors on a pathology specimen, the recommendation is not to use routine chemoradiation (which makes adjuvant therapy easier to tolerate), since there is no obvious benefit from the additional systemic therapy.
The third section we looked at is the use of induction chemotherapy. Induction chemotherapy is a controversial topic, and we have experts arguing for and against it. We spent a lot of time on this specific topic and did a careful review of the literature. We recommended that induction chemotherapy not be routinely used in the management of patients with oropharyngeal cancer, because the three trials that have tested this in a prospective randomized fashion were all negative.
The fourth section of the guideline focused on how to deliver the radiation treatment. For patients who have locally advanced disease who can’t receive chemotherapy, we recommended what we call “altered fraction radiation,” which can be delivered either in a more accelerated fashion for 6 weeks or delivered with twice-a-day hyperfractionation. We didn’t recommend one over the other but just assessed and described the literature supporting improved local control with both regimens in advanced disease. In summary, those are the big highlights of the guideline with respect to managing patients with oropharyngeal cancer.
3. You mentioned that there has been a recent uptick in patients diagnosed with HPV-positive oropharyngeal cancer, yet the new guideline mentions not basing treatment on HPV status of the patient’s tumor. Can you talk about that?
DR. SHER: This is an important point. As a panel and as a community, we clearly recognize that HPV-positive patients do substantially better than HPV-negative patients, especially when you look at the improving prognosis over the years. The new staging system now reflects this. But the key point is that these outcomes have been achieved with standard therapies that have been recommended in the guideline. When thinking about the purpose of the guideline-to use the evidence to recommend standard therapies-it was very clear from the start that there are insufficient data to support deviating from these standard treatments even in the most favorable cases of oropharyngeal cancer, specifically the HPV-positive nonsmokers. We are all very excited about, and are enthusiastically supportive of, entering clinical trials and testing different modalities of de-escalation and de-intensification, but those are trial-based therapies, and we wanted explicitly to make the point that standard therapies are recommended for all patients in standard practice.
4. Are there any ongoing clinical trials that have the potential to be practice-changing-that you and your colleagues are looking forward to reading about?
DR. SHER: That is a great question, and we as a panel strongly encourage all patients to enroll in these de-escalation trials. Given the favorable prognosis of HPV-positive patients and the toxicity associated with therapy, there are different paradigms to reduce the intensity of therapy, and they run the gamut. There is a Radiation Therapy Oncology Group trial that should be coming out in a few years that is evaluating a change in chemotherapy from cisplatin to cetuximab, and there are parallel trials in the United Kingdom and Australia looking at the same thing.
There are approaches to using induction chemotherapy, and then selecting responders to de-intensify the radiation. That approach has actually been published already, and certain aspects of that paradigm seem to be satisfying, safe, and potentially useful. There are other cooperative group trials in the United States: one is called NRG-HN002, which is lowering the dose, to try to reduce the overall intensity of the radiation treatment-and that concept may be carried out through other cooperative group trials.
Surgeons are getting into it too and have some exciting trials in which they are de-escalating the dose of the postoperative radiation in certain scenarios (there is a well-known trial, ECOG 3311, by the Eastern Cooperative Oncology Group that is attempting that), or just dropping the chemotherapy altogether in the patients with the lowest risk, the HPV-positive population.
The flip side to these are the dose-intensification trials, and I think it’s very important to remember that HPV-negative disease is almost like an orphan disease now, and there is some hope to use more novel systemic therapies like immunotherapy to increase the local control in this population as well.
Financial Disclosure:The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
Note: This interview was originally published online at Cancer Network, April 27, 2017.